DESCRIPTION (applicant's abstract): Synaptic transmission mediated by monoamines is terminated by cocaine-sensitive transporters. Transporter proteins limit the spread of transmitter and thus the activation of monoamine receptors to structures near release sites. By blocking reuptake, cocaine prolongs the duration of action and increases the volume over which monoamines act. The activation of pre- and post-synaptic monoamine receptors can (1) have directs on excitability, (2) alter the release of transmitters such as GABA and glutamate, and (3) alter postsynaptic sensitivity to non-monoamine transmitters. By affecting the activity of non-monoamine neurons, cocaine can cause adaptations in synaptic transmission that may seem only indirectly related to the inhibition of monoamine reuptake. Some of these adaptations may only be observed after repeated administration of cocaine. One aim of this proposal is to determine how cocaine modulates the release of GABA and glutamate in the Ventral Tegmental Area (VTA) in saline and psychostimulant treated animals. The primary hypothesis is that during withdrawal from cocaine treatment there is an increase in extracellular adenosine that decreases the release of GABA and glutamate through activation of presynaptic adenosine A1-receptors. A second aim is to determine how cocaine modulates the postsynaptic sensitivity of metabotropic glutamate receptors (mGluRs). The mGluR transduction pathway that mediates inhibition of dopamine cells is sensitive to psychostimulants. The hypothesis is that repeated administration of psychostimulants will result in adaptive changes in this complex and sensitive second messenger pathway that will change the excitability and pattern of dopamine cell activity in response to synaptically releases glutamate. This study will focus on the interaction between psychostimulants and the two major transmitters in the CNS, GABA and glutamate. Knowledge of these interactions is critical to develop an understanding of how cocaine mediates long term plasticity in a brain area involved in endogenous reward.